Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Levodopa is currently the standard of care treatment for Parkinson’s disease, but chronic therapy has been linked to motor complications. Designing a controlled release formulation (CRF) that maintains sustained and constant blood concentrations may reduce these complications. Still, it is challenging due to levodopa’s pharmacokinetic properties and the notion that it is absorbed only in the upper small intestine (i.e., exhibits an “absorption window”). We created and validated a physiologically based mathematical model to aid the development of such a formulation. Analysis of experimental results using the model revealed that levodopa is well absorbed throughout the entire small intestine (i.e., no “absorption window”) and that levodopa in the stomach causes fluctuations during the first 3 h after administration. Based on these insights, we developed guidelines for an improved CRF for various stages of Parkinson’s disease. Such a formulation is expected to produce steady concentrations and prolong therapeutic duration compared to a common CRF with a smaller dose per day and a lower overall dose of levodopa, thereby improving patient compliance with the dosage regime.


Sinemet CR 200mg individuals
In this section, we describe the blood concentrations of healthy individuals following the administration of Sinemet CR 200mg taken from Arav et al. 2 .Figure S1 shows levodopa blood concentrations in 7 individuals following administration of Sinemet CR 200/50mg (200 mg levodopa and 50mg Carbidopa, an Aromatic L-Amino acid Decarboxylase).The individuals were non-smoking healthy male subjects (ages 18-55) 2 , and fasted for at least 10 hours before administration.The concentration-time profiles of levodopa in 5 subjects (individuals 1,2,3,6,7) exhibit similar behavior.Specifically, the maximal concentrations 1 and double peaks were seen in the first 3 hours.The other 2 subjects (individuals 4 and 5) exhibit a delayed and slow absorption, with maximal concentrations obtained 4 to 5 hours after administration.In all subjects, the half-life time of the decay of levodopa in the blood is 1.5 hours, which is the characteristic decay rate of levodopa following concomitant administration with AADC inhibitor 3 .The occurrence of double peaks in blood concentrations following oral administration of levodopa is well documented in the literature and was attributed to an erratic gastric emptying [4][5][6] .

2
These results show that the rise, peak magnitude and location, and decay of the mean levodopa blood concentrations are similar to those observed in the individuals.Therefore, we can conclude that the mean concentrations of levodopa in the blood accurately represent the kinetics of levodopa in the individuals.

Sinemet CR 100mg individuals
In this section, we describe the blood concentrations of healthy individuals following the administration of Sinemet CR 100mg taken from Arav et al. 2 .Figure S2 shows levodopa blood concentration in 8 individuals following administration of Sinemet CR 100/25mg (100mg levodopa and 25mg Carbidopa, an Aromatic L-Amino acid Decarboxylase).The individuals were non-smoking healthy male subjects (ages 18-55) 2 , and fasted for at least 10 hours before administration.
In all the individuals, the peak levodopa blood concentrations are obtained within the first hour after administration.In 4 of the 8 individuals (numbers 1,4,5, and 8), the concentration-time profile exhibits a double peak, where the second peak is smaller than the first.In 7 of the 8 individuals (numbers 1,2,3,4,5,7, and 8), the concentrations decay smoothly after 2 hours.Individual 6 exhibited a small rise in the blood concentrations after 4 hours before the concentrations decayed.These results show that the rise, peak magnitude and location, and decay of the mean levodopa blood concentrations are similar to those observed in the individuals.Therefore, we can conclude that the mean concentrations of levodopa in the blood accurately represent the kinetics of levodopa in the individuals.

This section describes healthy individuals' blood concentrations after administering 200mg
Enteric-coated controlled release formulation taken from Flashner et al. 7 .
Figure S3 shows the concentration-time profile of the 12 individuals.Except for individual 6, the concentration-time profiles of the individuals share a close resemblance to each other.Specifically, the rise in the concentrations begins approximately 2 hours 4 after administration, exhibits a single peak after 4 to 6 hours, and then a decay in the concentrations.
These results show that the rise, peak magnitude and location, and decay of the mean levodopa blood concentrations are similar to those observed in the individuals.Therefore, we can conclude that the mean concentrations of levodopa in the blood accurately represent the kinetics of levodopa in the individuals.The effect of stomach emptying on levodopa blood concentrations The mean experimental blood concentrations following administration of Sinemet CR exhibit large variability in healthy and Parkinsonian patients during the first 3 hours after administration (Figure S4).It has been suggested that large inter-and intra-variability in the stomach emptying process.To further test this hypothesis, we conducted simulations with different parameters for stomach emptying.Specifically, we selected the stomach emptying rate, the lag duration, and the tablet's residence time in the stomach.
The values examined were taken from the range reported in the literature for these parameters 6,8 .S1

Figure S2 .
Figure S2.Experimental Concentration time profile following administration of Sinemet CR 100/50mg to healthy subjects.Taken from Arav et al. 2 .

Figure S3 .
Figure S3.Experimental Concentration time profile following administration of Entericcoated controlled release 200mg to healthy subjects.Taken from 7 .

Figure
Figure S4 depicts the effect of stomach emptying parameters on levodopa blood concentrations.Large variability is observed during the first 3 hours.The stomach emptying rate and the tablet residence time determine the rise of levodopa blood concentrations and the location of the second peak, while the duration of the lag determines the depth of the double peak.Note, that the absence of lag removes the double peak (Figure S4, simulation 1).

Figure S4 .
Figure S4.The effect of gastric emptying parameters on levodopa blood concentrations following Sinemet CR 200mg administration.The parameters of the simulations are given in TableS1